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  Delayed release carnitineRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Particulate Form (e.g., Powders, Granules, Beads, Microcapsules, And Pellets), Coated (e.g., Microcapsules)Delayed release carnitine description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060013887, Delayed release carnitine. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation-in-part of U.S. Ser. No. 08/078,985, filed Jun. 16, 1993, which is hereby incorporated by reference. TECHNICAL FIELD [0002] The invention relates to the field of sustained release pharmaceutical preparations and more specifically to a sustained release pharmaceutical preparation containing L-carnitine or gamma butyrobetaine. BACKGROUND OF THE INVENTION [0003] L-carnitine 3-hydroxy-4-(trimethylamino-)butyrate is a naturally occurring quaternary amine that is required in energy metabolism in mammals. The L-carnitine molecule has been shown to promote oxidation of branched-chain amino acids, the utilization of acetyl-coenzyme A, and the removal of extra or "toxic" acyl groups from the mitochondria and cell as carnitine esters. Arguably its most important function, however, is the promotion of beta-oxidation of long-chain fatty acids by facilitating their transfer across the mitochondrial membrane. [0004] Because of its central role in transporting fatty acids to the site of oxidation, adequate levels of L-carnitine are required for normal fatty acid and energy metabolism in those tissues, such as the heart, which preferentially metabolize fatty acids. In the human, L-carnitine is synthesized endogenously from the amino acids, lysine and methionine. Meat products, particularly red meats (beef, lamb and pork) and dairy products are important dietary sources of L-carnitine. None-the-less, carnitine deficiency can occur in humans and presents a characteristic syndrome. Affected individuals may display mild to severe muscle weakness, hypoglycemia, liver dysfunction and cardiomyopathy. If detected early, the syndrome is often completely reversible with daily administration of adequate amounts of L-carnitine. [0005] Gamma-butyrobetaine ("GBB") is the immediate precursor to L-carnitine in the biosynthetic pathway of the latter compound. It is disclosed in U.S. Pat. No. 4,382,092, incorporated herein by reference, that GBB given orally will be readily converted to L-carnitine in carnitine deficient patients and is thus a suitable substitute for L-carnitine in treating such deficiencies. GBB has the advantage of being much less expensive to chemically synthesize than is L-carnitine. Hereafter, the term "carnitine" will be understood to refer to either L-carnitine or GBB, as well as their biologically active salts and esters, but not D-carnitine, the latter compound being hereby specifically excluded. [0006] Some forms of organic aciduria have been treated with L-carnitine administration. In some such cases the affected individual must be given as much as 400 mg/k/day of L-carnitine. [0007] Carnitine is also considered by some authorities to be a useful and important nutritional supplement, particularly for older persons who frequently show elevated esterified carnitine levels in the serum. Some evidence exists that carnitine supplementation enhances the immune system, muscle efficiency, and overall well being of the person using carnitine supplementation. [0008] More recently, it has been found that carnitine is useful in patients suffering from or predisposed to osteoporosis. In such individuals it is believed that daily administration of carnitine will reduce the loss of bone mass. Co-pending U.S. application Ser. No. 07/907,847, incorporated herein by reference, discloses that daily administration of carnitine in amounts from 50 to 200 mg/kilogram will result in a significantly reduced loss of bone mass. [0009] Oral formulations of L-carnitine are available in tablet or capsule form. The inventors are not aware of any commercially available oral dosage formulation of GBB. None of the heretofore known oral formulations of L-carnitine provide a sustained release of L-carnitine. Common dosage forms of the presently available oral formulations are usually 250 to 500 mg per tablet or capsule. Principal suppliers of pharmaceutical grade L-carnitine are Sigma Tau SpA, Rome, Italy; Aginomoto, Terrance, Calif.; and Lanza Chemical Company, Berne, Switzerland. [0010] Where L-carnitine is being administered to treat carnitine deficiency dosages as high as 400 mg/K/day may have to be given. The customary dosage amount for mild to moderate carnitine deficiency is 50 to 100 mg/k/day. [0011] Because the half-life L-carnitine in the human is approximately 30 minutes, the usual dosage regimen is to administer an excess amount of L-carnitine four times each day. If the dosage formulation is 250 mg/tablet, one would expect a 70 kilogram mildly deficient individual to take 7 tablets, four times each day (or 28 tablets/day) in order to restore L-carnitine to normal plasma levels. [0012] A number of disadvantages exist with the presently available dosage forms of L-carnitine. First, the renal threshold for L-carnitine is about 80 to 120 microM/L. This threshold is invariably exceeded when large amounts of L-carnitine are given and thus much of the otherwise useful L-carnitine is "dumped" in the urine. Second, L-carnitine is subject to breakdown by the bacteria of the gut and when large boluses of the drug are given, a fair amount is lost through bacterial breakdown. Third, L-carnitine can cause gastrointestinal irritation resulting in gastrointestinal distress and diarrhea. Such problems are exacerbated when frequency of administration and dosage levels are both high. [0013] The present invention avoids most, if not all, of the above stated disadvantages. Additionally, it allows for a much more convenient dosage regimen (e.g., once or twice per day) with greater efficacy than its nonsustained release counterpart. SUMMARY OF THE INVENTION [0014] The present invention provides an oral formulation of carnitine which virtually eliminates the above recited problems of dumping of carnitine in the urine, bacterial breakdown of carnitine by intestinal bacteria, and gastrointestinal distress and diarrhea when daily administration of large amounts of L-carnitine are recommended. Using the invention, methods of treating various carnitine responsive disorders are disclosed. [0015] Accordingly, it is an object of this invention to provide a sustained release carnitine drug preparation useful in the treatment or prevention of L-carnitine deficiency or other L-carnitine responsive disorders, such as osteoporosis, which does not cause adverse GI symptoms, such as gastrointestinal distress and diarrhea. [0016] It is a specific object of this invention to provide a sustained release, unitary dosage, oral formulation of carnitine which upon administration releases carnitine at a slow rate over the course of at least several hours, preferably a maximum of eight hours without causing the gastrointestinal irritation. [0017] It is another object of the invention to provide a method for treating or preventing L-carnitine deficiency by administering, at least once daily, to a patient suffering from or at risk for L-carnitine deficiency, a sustained release, unitary dosage product containing sufficient amount of carnitine effective to increase the serum L-carnitine to normal level. [0018] It is a further object of the invention, to provide a method for treating or preventing carnitine responsive, age-related disorders, such as osteoporosis, by administering, at least once daily, to a patient suffering from or predisposed to said carnitine responsive, age-related disorder a sustained release, unitary dosage formulation of carnitine (alone or in combination with one or more other active ingredients) effective for the maintenance of or formation and strengthening of diseased or weakened tissues such as muscle and bone. [0019] In accordance with these objectives and other objects, which will become apparent from the following description, the present invention provides, in one aspect thereof, a medication for providing carnitine for the treatment or prevention of L-carnitine deficiency or osteoporosis, which is in the form of a unitary dosage formulation containing from about 100 milligrams (mg) to about 500 mg of carnitine. The formulation of the invention further includes a means for slowly releasing the aforesaid active ingredient(s) over a period of several to eight hours upon exposure to the gastrointestinal fluids. The formulation of the invention is designed to release carnitine at such a rate that the quantity of carnitine present in the stomach or intestine at any one time is below the amount likely to cause gastrointestinal irritation. The slowly released carnitine is readily absorbed and exposes less carnitine to bacterial degradation. The formulation of the invention is further designed so that the dosage of carnitine is slowly absorbed over period of several to eight hours. This controlled absorption of carnitine over a period of hours limits the loss of carnitine due to dumping in the urine and thus makes more of the carnitine in the formulation available for use by the body. [0020] The sustained release unitary dosage product of this invention may include L-carnitine or GBB as the sole active ingredient. Alternatively, L-carnitine or GBB may be used together in varying proportions, or one or the other may be used in combination with other active ingredients when used to treat other L-carnitine responsive age-related conditions such as osteoporosis. In the latter case, co-pending U.S. patent application Ser. No. 08/078,985, incorporated herein by reference, discloses the combination of L-carnitine or GBB and the hormone dehydroepiandrosterone or dehydroepiandrosterone-sulfate (hereafter referred to collectively as "DHEA") as a useful and desirable combination. [0021] In a specific and preferred embodiment of the invention, the means for controlling release of carnitine and any other active ingredient includes a matrix of water swelling polymerization products. In the preferred embodiment, these products are acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. The aforesaid polymerization products form a thin lacquer which completely coats small granules of the carnitine or GBB and other active ingredients if present. The polymer coating is water insoluble but slowly permeable. Upon introduction of the unitary dosage product into an aqueous medium, the polymeric coating swells and allows water to slowly permeate the preparation. Carnitine or GBB, both of which are highly water soluble, are dissolved in the slowly permeating water thereby slowly and uniformly released into the gastrointestinal tract. Continue reading about Delayed release carnitine... 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